Arformoterol tartrate is the United States Adopted Name (USAN) for (R,R) formoterol L-tartrate. The chemical name for arformoterol tartrate is formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-, (2R,3R)-2,3dihydroxybutanedioate (1:1 salt), and is represented by formula (Ia):

Arformoterol tartrate is currently marketed in the United States under the trade name BROVANA®. BROVANA® (arformoterol tartrate) Inhalation Solution is supplied as 2 mL of arformoterol tartrate solution packaged in 2.1 mL unit-dose, low-density polyethylene (LDPE) unit-dose vials. Each unit-dose vial contains 15 mcg of arformoterol (equivalent to 22 mcg of arformoterol tartrate) in a sterile, isotonic saline solution, pH-adjusted to 5.0 with citric acid and sodium citrate.
U.S. Pat. No. 6,472,563 discloses polymorphic Form A, B and C of arformoterol L-(+)-tartrate. The specification recites that the product described in the art, U.S. Pat. No. 6,268,533 as it initially crystallizes, contains four identified chemical impurities and no matter how many times the product is recrystallized the resultant polymorph A contains at least 0.5% of impurities. Further the specification of US'563 discloses that conditions of recrystallization may result in partial hydrolysis and lead to the formation of impurities and that it may be possible that some degradation occurs and impurities are introduced in the recrystallization process.
For the development of an active pharmaceutical ingredient two factors are important namely the impurity profile of the active pharmaceutical ingredient and the polymorphic Form that is to be targeted. The known art discloses that crystallization conditions and method of isolation of Arformoterol L-(+)-tartrate may lead to varied polymorphic Forms A, B, C or mixtures thereof with different levels of impurities, compounds of Formula A, B, C and/or D.

The art discloses that polymorphic Form B of Arformoterol L-(+)-tartrate can be obtained in a crude state only and attempts to improve the chemical purity of Form B by altering the temperature and ratios of solvents leads to interconversion to polymorphic Form C. The temperature and the ratios of solvents used are not only critical for removal of chemical impurities but important for crystal morphology also. Thus when optimization of chemical purity of Arformoterol L-(+)-tartrate occurs, the polymorphic Form B does not remain same and is converted to Form C. Thus the state of art does not disclose a process for the preparation of Arformoterol L-(+)-tartrate in polymorphic Form B and substantially free of impurities, compounds of Formula A, B, C, D and/or E.

The process of conversion of crude arformoterol to arformoterol L-(+)-tartrate, in the art entails use of specific solvent systems to meet the desired standards of chemical, chiral and polymorphic Form purity but is still unable to obtain polymorphic Form B in desired chemical purity and uncontaminated with other polymorphic Forms.
We have also found that when crude arformoterol base is subjected to reaction with L (+) tartaric acid in a solvent, the arformoterol L-(+)-tartrate cannot be obtained in desired polymorphic Form B and chemical purity and is contaminated with other polymorphic forms. Further, when crude arformoterol base with impurities, compounds of Formula A, B, C, D and/or E is subjected to reaction with L (+) tartaric acid in aqueous tetrahydrofuran system, to improve the chemical and chiral purity, the arformoterol L-(+)-tartrate cannot be obtained in desired chemical purity and polymorphic Form B and is usually contaminated with other polymorphic forms.
Therefore, there is a need for an improved process for the preparation of arformoterol L-(+)-tartrate in desired single polymorphic Form B, uncontaminated with other polymorphic Forms A and C and substantially free of impurities, compounds of Formula A, B, C, D and/or E. The need in the art is to provide a reliable and reproducible process to prepare consistently the desired polymorphic Form B of arformoterol L-(+)-tartrate having a chemical purity of at least 99% and a chiral purity of at least 99% without using chromatographic purification techniques.
The present invention provides a process which is simple, ecofriendly, inexpensive, reproducible, robust and well suited on commercial scale and circumvents the likely formation of isomeric and other process-related impurities; while ensuring a target polymorphic form of arformoterol tartrate product with optimum yield and polymorphic and chemical purity.
In the process of the present invention, the crude arformoterol is reacted with D-(−)-tartaric acid to form arformoterol D-(−)-tartrate, which is then reacted with a base and L-(+)-tartaric acid to provide high purity arformoterol L-(+)-tartrate. Surprisingly, we have found that the present process via arformoterol D-(−)-tartrate affords high purity arformoterol L-(+)-tartrate, substantially free of impurities, compounds of Formula A, B, C, D and/or E and in desired polymorphic Form B, in contrast to the known method of conversion of crude arformoterol to arformoterol L-(+)-tartrate by reacting it with L-(+)-tartaric acid.